Huntington's disease (HD) is a chronic neurodegenerative disease resulting from an autosomal dominant mutation in the gene for the huntingtin protein (htt). It is unknown, however, how mutant huntingtin causes a stereotyped pattern of neuronal loss, nor why it is particularly toxic to the medium spiny neurons (MSNs) of the striatum. MicroRNAs (miRNAs) are small nucleic acids which disrupt translation of target messenger RNAs and sometimes accelerate their degradation. We will determine whether aberrant levels of specific miRNAs correlate with the pathology of HD. Subsequently, we will determine if an excess or deficiency of a specific species of microRNA causes HD pathology. We propose an experimental agenda with three lines of investigation: 1) Identifying miRNAs vary in the HD neural tissue and cells expressing mutant huntingtin. We will evaluate brains from HD humans and mice as well as from cellular models of HD. 2) Determining if dysregulated microRNAs sensitize neurons to cell death from environmental stress. 3) Identifying relevant targets of microRNA mediated neuronal toxicity. The field of miRNA biology is novel and expanding;its application to the study of HD is in its infancy. Consequently, we expect our investigations to contribute novel ideas to the understanding of the pathology of HD. The ultimate goal of this project is therefore to both better understand microRNA physiology and pathophysiology, particularly in a neurodegenerative disease, as well as to develop microRNA-based therapeutics for this devastating and untreatable disease.